Mice with an excess of liver X receptor (LXRa), when fed a diet high in fat, remained free from the high cholesterol and blood vessel plaques exhibited by animals with the normal complement of receptors. Remarkably, in mice fed a normal, balanced diet, the excess receptors worsened blood lipid levels, the researchers reported.
The findings suggest that natural variation among individuals in the quantity of the liver receptors might lead to differences among them in their susceptibility to high cholesterol and heart disease in a manner dependent on diet. Furthermore, drugs that modulate LXRa activity may have potential as therapies for lipid disorders and atherosclerosis, the group said.
"The high-cholesterol, high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascular disease, making it the leading cause of death in industrialized nations," said study senior author Mitchell Lazar, of the University of Pennsylvania School of Medicine. "Yet we know that some people are more susceptible than others to obesity and other problems of excess, suggesting that the interplay between genes and diet is important.
"Now we have a vivid example of a specific genetic alteration with opposite effects in different nutritional environments."
The researchers examined lipid metabolism and atherosclerosis in mice with an approximately 3-fold increase in the concentration of LXRa receptors in their livers. The mice also lacked a second gene that made them particularly prone to cardiovascular disease.
When fed normal mouse chow, mice with a greater than average number of the receptors exhibited a rise in blood cholesterol and triglyceride levels. In contrast, altered mice fed a high-fat, Western diet showed improvements in blood lipid levels and protection from atherosclerosis.
Further experimentation revealed that the increase in LXRa differentially regulated the expression of other important metabolic genes.
"Liver X receptors had emerged as key regulators of cholesterol and lipid metabolism," said Lazar. "The current study elucidates a previously unrecognized role for these liver receptors in the links between diet, serum lipids, and atherosclerosis."
Selective modulation of the LXR target genes in liver may therefore ameliorate high lipid levels and cardiovascular disease, the researchers said.
The researchers include Michael Lehrke, Corinna Lebherz, Segan Millington, Hong-Ping Guan, John Millar, Daniel J. Rader, James M. Wilson, and Mitchell A. Lazar of the University of Pennsylvania School of Medicine. This work was supported by NIH grants, the Penn Diabetes and Endocrinology Research Center, and a Bristol Myers Squibb Freedom to Discover Award in Metabolic Research. M.L. was supported by a Deutsche Forschungsgemeinschaft fellowship.
Lehrke, M., Lebherz, C, Millington, S., Guan, H.-P., Millar, J., Rader, D.J., Wilson, J.M., and Lazar, M.A. (2005). Diet-dependent cardiovascular lipid metabolism controlled by hepatic LXRalpha. Cell Metab. 1, 297-308.